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Chaperone-mediated autophagy maintains glioma stem cell activity controlling different proteomic and transcriptomic pathways (U251)

ABSTRACT: Chaperone-mediated autophagy (CMA) is a homeostatic process essential for the lysosomal degradation of individual proteins. CMA activity directly depends on the levels of LAMP2A, critical receptor at the lysosomal membrane, to which CMA substrate proteins are bound. In glioblastoma (GBM), the most common and aggressive brain cancer in the adulthood, high levels of LAMP2A have been linked to TMZ resistance and tumor-associated pericytes. However, the implication of LAMP2A, and hence CMA, in glioblastoma stem cells (GSCs) remains unknown. In this work, we show that LAMP2A expression is enriched in patient-derived GSC population and its knock-down diminishes GSCs tumorigenic activities. Proteomic and transcriptomic analysis of LAMP2A knocked-down GSCs revealed reduced extracellular matrix (ECM) interaction effectors in both analyses. Moreover, immune system and mitochondrial metabolism related pathways were remarkably deregulated at proteome level, whereas PI3K-AKT and p53 pathways were altered in RNAseq study. Moreover, clinical samples of GBM tissue presented overexpression of LAMP2 and its high levels correlated with advanced glioma grade and poor overall survival. In conclusion, we identified a novel role of CMA directly regulating GSCs activity via multiple pathways at proteome and transcriptome level.

INSTRUMENT(S): timsTOF Pro

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Stem Cell, Cell Culture

DISEASE(S): Glioblastoma

SUBMITTER: Mikel Azkargorta

LAB HEAD: Félix Elortza

PROVIDER: PXD029393 | Pride | 2022-08-02

REPOSITORIES: Pride

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Chaperone-mediated autophagy maintains glioma stem cell activity controlling different proteomic and transcriptomic pathways

Project description:Chaperone-mediated autophagy (CMA) is a homeostatic process essential for the lysosomal degradation of individual proteins. CMA activity directly depends on the levels of LAMP2A, critical receptor at the lysosomal membrane, to which CMA substrate proteins are bound. In glioblastoma (GBM), the most common and aggressive brain cancer in the adulthood, high levels of LAMP2A have been linked to TMZ resistance and tumor-associated pericytes. However, the implication of LAMP2A, and hence CMA, in glioblastoma stem cells (GSCs) remains unknown. In this work, we show that LAMP2A expression is enriched in patient-derived GSC population and its knock-down diminishes GSCs tumorigenic activities. Proteomic and transcriptomic analysis of LAMP2A knocked-down GSCs revealed reduced extracellular matrix (ECM) interaction effectors in both analyses. Moreover, immune system and mitochondrial metabolism related pathways were remarkably deregulated at proteome level, whereas PI3K-AKT and p53 pathways were altered in RNAseq study. Moreover, clinical samples of GBM tissue presented overexpression of LAMP2 and its high levels correlated with advanced glioma grade and poor overall survival. In conclusion, we identified a novel role of CMA directly regulating GSCs activity via multiple pathways at proteome and transcriptome level.

2023-03-11 | PXD027069 | Pride

Identification of novel BMP target genes in glioblastoma

Project description:It has been previously described that in glioblastoma (GBM), BMPs deplete the tumorigenic potential of glioblastoma stem cells (GSCs), promoting their differentiation towards the astrocytic lineage. To gain more insight on how BMPs regulate differentiation in GSCs, we are interested in identifying new BMP target genes in GBM cells. To this end, the patient derived glioblastoma cell lines U3031MG and U3034MG were stimulated or not with 30ng/ml BMP7 for 2 and 24 h, total RNA was isolated from three biological replicates per condition, and a microarray screen with the Affymetrix U133plus2 platform was performed.

2021-05-01 | E-MTAB-9811 | biostudies-arrayexpress

ZNF117 target ChIP-seq

2022-02-08 | GSE196067 | GEO

Transforming growth factor β (TGFβ) and BMP7 regulate glioblastoma stem cells differentiation status

Project description:Glioblastoma stem cells (GSCs) fate is controlled by environmental cues, among which cytokines play a crucial role. The transforming growth factor β (TGFβ) family signaling pathways controls GSCs. On one hand, TGFβ promotes cell proliferation in GBM, it induces the expression of platelet-derived growth factor-B (PDGFB). Moreover, TGFβ, via its signaling mediators Smad2/3, induces the expression of the cytokine leukemia inhibitory factor (LIF) and Sox4, which in turn enhances the expression of the stem cell transcription factor Sox2; this increases the self-renewal capacity of the GSCs and their stemness characteristics, and enhances the GSC tumor-initiating potential. On the other hand, Bone morphogenic proteins (BMPs) are known to promote GSC differentiation towards the astrocytic phenotype. To further understand which genes are regulated by TGFβ and BMP7 in GSCs we performed a microarray in the Affymetrix HTA2 platform in three different glioblastoma cell line, U2987, and two patient-derived glioblastoma stem cells, U3031MG and U3034MG, in the presence or absence of 5 ng/ml of TGFβ or 30 ng/ml BMP7 for 24 h, three biological replicates per condition.

2020-09-01 | E-MTAB-9076 | biostudies-arrayexpress

Glioma stem cell treatment with MELK-signaling inhibitors

Project description:Glioblastoma multiforme (GBM) is a highly lethal brain tumor. Due to resistance to current therapies, patient prognosis remains poor and development of novel and effective GBM therapy is crucial. Glioma stem cells (GSCs) have gained attention as therapeutic target in GBM due to their relative resistance to current therapies and potent tumor-initiating ability. Recent studies including our own identified that the mitotic kinase, maternal embryonic leucine-zipper kinase (MELK), is highly expressed in GBM tissues, specifically in GSCs, and its expression is inversely correlated with the post-surgical survival period of GBM patients. In addition, patient-derived GSCs depend on MELK for their survival and growth both in vitro and in vivo. Here, we provide evidence that the kinase activity of MELK is essential for the action of MELK in GSCs and vital for GBM growth. We utilized in silico structure-based analysis for protein-compound interaction to predict that a recently identified small molecule, Compound 1 (C1), binds to the kinase-active site of MELK protein and eliminates MELK kinase activity in nanomolar concentrations. When treated with C1, GSCs undergo mitotic arrest and subsequent cellular apoptosis in vitro, a phenotype identical to that observed using MELK shRNA-mediated knockdown. C1 treatment strongly induces tumor cell apoptosis in slice cultures of GBM surgical specimens and attenuates growth of mouse intracranial tumors derived from GSCs in a dose-dependent manner. Lastly, C1 treatment sensitizes GSCs to radiation treatment. Collectively, these data indicate that targeting MELK kinase activity is a promising approach to attenuate GBM growth by eliminating GSCs in tumors. Microarray-based expression analysis of glioma stem cells treated with MELK-signaling inhibitors

2013-08-28 | E-GEOD-50227 | biostudies-arrayexpress

A Proneural to Mesenchymal Transition Mediated by NFkB Promotes Radiation Resistance in Glioblastoma (part 2)

Project description:SUMMARY Despite numerous genome-wide association studies involving glioblastoma (GBM), few therapeutic targets have been identified for this disease. Using patient derived glioma sphere cultures (GSCs), we have found that a subset of the proneural (PN) GSCs undergo transition to a mesenchymal (MES) state in a TNFa/NFkB dependent manner with an associated enrichment of CD44 sub-populations and radio-resistant phenotypes. To the contrary, MES GSCs exhibit constitutive NFkB activation, CD44 enrichment and radio-resistance. Patients whose tumors exhibit a higher MES metagene, increased expression of CD44, or activated NFkB were associated with poor radiation response and shorter survival. Our results indicate that NFkB activation mediated MES differentiation and radiation resistance presents an attractive therapeutic target for GBM. SIGNIFICANCE In this study, we show plasticity between the proneural (PN) and mesenchymal (MES) transcriptome signatures observed in glioblastoma (GBM). Specifically, we show that PN glioma sphere cultures (GSCs) can be induced to a MES state with an associated enrichment of CD44 expressing cells and a gain of radio-resistance, which we implicate as NFkB- dependent. Newly diagnosed GBM samples show a direct correlation between radiation response, higher MES metagene, CD44 expression, and NFkB activation. This correlation is also observed in the subset of GBM samples that do not exhibit IDH1 mutation, a favorable prognostic marker. Our results uncover a previously unknown link between subtype plasticity that is regulated by NFkB. Inhibition of NFkB activation can directly impact radio-resistance and presents an attractive therapeutic target for GBM. 4 treatments

2013-08-15 | E-GEOD-49162 | biostudies-arrayexpress

A Proneural to Mesenchymal Transition Mediated by NFkB Promotes Radiation Resistance in Glioblastoma (part 1)

2013-08-15 | E-GEOD-49161 | biostudies-arrayexpress

Dual role of Integrin alpha-6 in glioblastoma: supporting stemness in proneural stem-like cells while inducing radioresistance in mesenchymal stem-like cells

Project description:Therapeutic resistance after multimodal therapy is the most relevant cause of glioblastoma (GBM) recurrence. Extensive cellular heterogeneity, mainly driven by the presence of GBM stem-like cells (GSC), strongly correlates with patients’ prognosis and limited response to therapies. Defining the mechanisms which drive stemness and control responsiveness to therapy in a GSC-specific manner is therefore mandatory. Here we investigated the role of integrin a6 (ITGA6) in controlling stemness and resistance to radiotherapy in proneural and mesenchymal GSCs subtypes. Using cell sorting, gene silencing, RNA-Seq and in vitro assays, we verified that ITGA6 expression seems crucial for proliferation and stemness of proneural GSCs, while it appears not to be relevant in mesenchymal GSCs under basal conditions. However, when challenged with a fractionated protocol of radiation therapy, comparable to that employed in the clinical setting, mesenchymal GSCs turned out to be dependent on integrin a6 for survival. Specifically, GSCs with reduced levels of ITGA6 displayed a clear reduction of DNA-damage response and perturbation of cell cycle pathways. These data indicate that ITGA6 inhibition is able to overcome the radioresistance of mesenchymal GSCs, while it reduces proliferation and stemness in proneural GSCs. Therefore, integrin a6 controls crucial characteristics across GBM subtypes in GBM heterogeneous biology and thus may represent a promising target to improve patient outcomes

2021-06-30 | GSE178260 | GEO

Gene expression data of GBM146 and GBM157 at day0, 7, 30 after serum exposure

Project description:Glioblastoma (GBM) is a lethal brain cancer composed of heterogeneous cellular populations including glioma stem cells (GSCs) and their progeny differentiated non-stem glioma cells (NSGCs). Although accumulating evidence points out the significance of GSCs for tumour initiation and propagation, the roles of NSGCs remain elusive. Here we demonstrate that, when patient-derived GSCs in GBM tumours undergo differentiation with diminished telomerase activity and shortened telomeres, they subsequently become senescent phenotype, thereby secreting angiogenesis-related proteins, including vascular endothelial growth factors. Interestingly, these secreted factors from senescent NSGCs promote proliferation of human umbilical vein endothelial cells and tumorigenic potentials of GSCs in immunocompromised mice. These experimental data are likely clinically-relevant, since immunohistochemistry of both patient tumours of GBM and the patient GSC-derived mouse xenografted tumours detected tumour cells that express a set of markers for the senescence phenotype. Collectively, our data suggest that the inter-cellular signals from senescent NSGCs promote GBM tumour angiogenesis thereby increasing malignant progression of GBM. We monitored gene expression profiling in GSC, differentiated NSGC (GSC at day7 after serum exposure), and senescent NSGC (GSC at day30 after serum exposure) of GBM146 and GBM157.

2015-10-24 | E-GEOD-74304 | biostudies-arrayexpress

Human glioma stem cell GS5: Control vs. ZNF117 knockout

Project description:Glioblastoma (GBM) is a deadly disease without effective treatment. Because glioblastoma stem cells (GSCs) contribute to tumor resistance and recurrence, improved treatment of GBM can be achieved by eliminating GSCs through inducing their differentiation. Prior efforts have been focused on studying GSC differentiation towards the astroglial lineage. We used microarrays to detail the global programme of gene expression underlying ZNF117 knockout and identified distinct classes of up-regulated genes during this process.

2022-01-31 | GSE187418 | GEO

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